Congenital central hypoventilation syndrome (CCHS)
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Publication
Journal: Orphanet Journal of Rare Diseases
September/21/2020
Abstract
Background: Congenital Central Hypoventilation Syndrome (CCHS) is a rare condition characterized by an alveolar hypoventilation due to a deficient autonomic central control of ventilation and a global autonomic dysfunction. Paired-like homeobox 2B (PHOX2B) mutations are found in most of the patients with CCHS. In recent years, the condition has evolved from a life-threatening neonatal onset disorder to include broader and milder clinical presentations, affecting children, adults and families. Genes other than PHOX2B have been found responsible for CCHS in rare cases and there are as yet other unknown genes that may account for the disease. At present, management relies on lifelong ventilatory support and close follow up of dysautonomic progression. BODY: This paper provides a state-of-the-art comprehensive description of CCHS and of the components of diagnostic evaluation and multi-disciplinary management, as well as considerations for future research.
Conclusion: Awareness and knowledge of the diagnosis and management of this rare disease should be brought to a large health community including adult physicians and health carers.
Keywords: Central hypoventilation; Dysautonomia; Hirschsprung disease; Long-term ventilation; Neural crest tumour; PHOX2B.
Publication
Journal: Brain Pathology
July/12/2020
Abstract
Congenital central hypoventilation syndrome (CCHS) represents a rare genetic disorder usually caused by mutations in the homeodomain transcription factor PHOX2B. Some CCHS patients suffer mainly from deficiencies in CO2 and/or O2 respiratory chemoreflex, whereas other patients present with full apnea shortly after birth. Our goal was to identify the neuropathological mechanisms of apneic presentations in CCHS. In the developing murine neuroepithelium, Phox2b is expressed in three discrete progenitor domains across the dorsal-ventral axis, with different domains responsible for producing unique autonomic or visceral motor neurons. Restricting the expression of mutant Phox2b to the ventral visceral motor neuron domain induces a marked newborn apnea together with a significant loss of visceral motor neurons, RTN ablation, and preBötzinger complex dysfunction. This finding suggests that the observed apnea develops through non-cell-autonomous developmental mechanisms. Mutant Phox2b expression in dorsal rhombencephalic neurons did not generate significant respiratory dysfunction, but did result in subtle metabolic thermoregulatory deficiencies. We confirm the expression of a novel murine Phox2b splice variant which shares exons 1 and 2 with the more widely studied Phox2b splice variant, but which differs in exon 3 where most CCHS mutations occur. We also show that mutant Phox2b expression in the visceral motor neuron progenitor domain increases cell proliferation at the expense of visceral motor neuron development. We propose that visceral motor neurons may function as organizers of brainstem respiratory neuron development, and that disruptions in their development result in secondary/non-cell autonomous maldevelopment of key brainstem respiratory neurons.
Keywords: Nkx2.2; PHOX2B; Apnea; Chemosensation; Congenital central hypoventilation syndrome (CCHS); Respiratory rhythm-generating networks.
Publication
Journal: European Journal of Pediatrics
January/17/2020
Abstract
Congenital central hypoventilation syndrome (CCHS) patients are at risk for life-threatening cardiac arrhythmias, and presentation is dependent on their PHOX2B gene mutation. We describe the presentation of life-threatening arrhythmias in our cohort of CCHS patients. We reviewed the records of 72 CCHS patients seen at CHLA from 2004 to 2018. Data collected included demographics, PHOX2B genotype, ventilatory support, clinical symptoms, ambulatory cardiac monitoring results, and presence of cardiac pacemaker. Sixteen of 72 patients had evidence of potential life-threatening cardiac arrhythmias. PHOX2B genotypes were 20/25 polyalanine repeat expansion mutation (PARM), 20/26 PARM, 20/27 PARM, 20/32 PARM, and c.245C > T non-polyalanine repeat mutation. 11/16 patients were ventilated during sleep only. Symptoms included syncope, dizziness, chest pain, tingling in the left arm, and palpitations. 15/16 patients had recorded ambulatory cardiac monitoring. 5/16 patients were symptomatic without significant sinus pauses. 12/16 patients had implantation of cardiac pacemakers. 9/12 had significant sinus pauses on ambulatory monitoring, and 7/12 patients were symptomatic.Conclusion: CCHS patients have potential life-threatening arrhythmias requiring cardiac pacemaker implantation. Many of these patients are symptomatic with significant sinus pauses on ambulatory monitoring. However, some symptomatic patients with no significant pauses on ambulatory monitoring may still require cardiac pacemaker implantation.What is Known:• CCHS patients are at risk for life-threatening sinus pauses and require cardiac pacemaker implantation.What is New:• CCHS patients regardless of PHOX2B genotype are at risk for significant sinus pauses. Many CCHS patients with significant sinus pause on ambulatory cardiac monitoring are symptomatic and most present with syncope. Some symptomatic patients do not have significant sinus pauses but may still require cardiac pacemaker implantation.
Publication
Journal: Cureus
January/24/2020
Abstract
Congenital central hypoventilation syndrome (CCHS) is a critical and rare autosomal dominant disorder that was first described by Robert Mellins in 1970. CCHS is defined to be an autonomic nervous system (ANS) dysfunction that usually presents in the neonatal period with hypoventilation and dysregulated autonomic homeostasis on a multi-system level. Classically, CCHS presents with normal ventilation while awake, and hypoventilation with normal respiratory rate during sleep. CCHS has been causally linked to the paired-like homeobox 2B (PHOX2B) gene. We report the case of a full-term male infant diagnosed with CCHS at two months of age with repeated extubation failure secondary to CCHS. The patient was discharged at five months of age with a home ventilator.
Publication
Journal: Frontiers in Neurology
April/4/2021
Abstract
Heterozygous mutations in the Paired like homeobox 2b (PHOX2B) gene are causative of congenital central hypoventilation syndrome (CCHS), a rare monogenic disorder belonging to the family of neurocristopathies and due to a defective development of the autonomic nervous system. Most patients manifest sudden symptoms within 1 year of birth, mainly represented by central apnea and cyanosis episodes. The sudden appearance of hypoxic manifestations in CCHS and their occurrence during sleep resemble two other unexplained perinatal disorders, apparent life-threatening event (ALTE) and sudden and unexpected infant death (SUID), among which the vast majority is represented by sudden infant death syndrome (SIDS). Differently from CCHS, characterized by Mendelian autosomal dominant inheritance, ALTE and SIDS are complex traits, where common genetic variants, together with external factors, may exert an additive effect with symptoms likely manifesting only over a "threshold." Given the similarities observed among the three abovementioned perinatal disorders, in this work, we have analyzed the frequency of PHOX2B common variants in two groups of Italian idiopathic ALTE (IALTE) and SUIDs/SIDS patients. Here, we report that the c*PHOX2B (i) became overrepresented in the two sets of patients compared to population matched healthy controls, and (ii) associated with decreased PHOX2B gene expression, likely mediated by miR-204, a microRNA already known to bind the 3'UTR of the PHOX2B gene. Overall, these results suggest that, at least in the Italian population, the SNP c*PHOX2B expression down-regulation. However, these are preliminary observations that need to be confirmed on larger cohorts to achieve a clinical relevance.
Keywords: PHOX2B; gene expression regulation; idiopathic apparent life threatening event; miR-204; sudden infant death syndrome; sudden unexpected infant death.
Publication
Journal: Orphanet Journal of Rare Diseases
November/17/2020
Abstract
Background: Congenital Central Hypoventilation Syndrome (CCHS) is characterized by central hypoventilation due to abnormal autonomic control of breathing and global dysautonomia. Patients harbour heterozygous PHOX-2B gene mutations which are polyalanine repeats of various lengths in most of the cases. A few previous studies have reported learning difficulties and neuropsychological disorders in patients with CCHS. The aims of the present study were (1) to explore the intellectual abilities of a group of children with CCHS followed up in the centre of reference for CCHS in France using the Wechsler batteries of tests, (2) and to assess whether there was any association between CCHS characteristics and various domains of the intellectual functioning.
Results: There were 34 consecutive patients (15 males, 19 females) of mean (SD) age of 7.8 (3.8) years, ranging from 4 to 16 years and 6 months. Mean score of full-scale intelligence quotient was 82 (20), being in the low average range. Indexes of working memory and processing speed were significantly lower as compared to the other Wechsler indexes. There were two important findings: (1) full-scale intelligence quotient as well as indexes of verbal comprehension and processing speed were significantly greater in patients with mask ventilation than in those with tracheostomy ventilation (p = 0.012, 0.032 and 0.042 respectively); (2) most interestingly, in the patients with polyalanine repeats mutations, all intellectual indexes negatively correlated with the number of polyalanine expansion, with statistical significance reached for indexes of fluid reasoning and working memory (R = - 0.449, p = 0.032 and R = - 0.562, p = 0.012 respectively).
Conclusions: CCHS increased the risk to develop neurocognitive deficiencies, affecting particularly speed of processing and working memory. Our results suggested that both genetics and ventilation method could be also involved in the physiopathology of neurocognitive impairment. Further investigations were required to untangle the complex underlying processes. Neurocognitive assessments should be performed regularly in children with CCHS in order to plan re-education programs, adapt school integration and improve quality of life.
Keywords: Autonomous nervous system; Congenital Central Hypoventilation Syndrome; Neurocognition; PHOX-2B; Processing speed; Working memory.
Publication
Journal: BMC Pediatrics
May/7/2020
Abstract
Congenital central hypoventilation syndrome (CCHS) is a rare disorder characterized by respiratory system abnormalities, including alveolar hypoventilation and autonomic nervous system dysregulation. CCHS is associated with compromised brain development and neurocognitive functioning. Studies that evaluate cognitive skills in CCHS are limited, and no study has considered cognitive abilities in conjunction with psychosocial and adaptive functioning. Moreover, the roles of pertinent medical variables such as genetic characteristics are also important to consider in the context of neurocognitive functioning.Seven participants with CCHS ranging in age from 1 to 20 years underwent neuropsychological evaluations in a clinic setting.Neurocognitive testing indicated borderline impaired neurocognitive skills, on average, as well as relative weaknesses in working memory. Important strengths, including good coping skills and relatively strong social skills, may serve as protective factors in this population.CCHS was associated with poor neurocognitive outcomes, especially with some polyalanine repeat expansion mutations (PARMS) genotype. These findings have important implications for individuals with CCHS as well as medical providers for this population.
Publication
Journal: Stem Cell Research
August/21/2020
Abstract
Congenital central hypoventilation syndrome (CCHS) is a rare life-threatening condition affecting the autonomic nervous system that usually presents shortly after birth as hypoventilation or central apnea during sleep. In the majority of cases, heterozygous polyalanine expansion mutations within the third exon of the paired-like homeobox 2B (PHOX2B) gene underlie CCHS. Here, we report the generation of two induced pluripotent stem cell (iPSC) lines from two identical twins with a heterozygous PHOX2B expansion mutation (+5 alanine residues). Both generated lines highly express pluripotency markers, can differentiate into the three germ layers, retain the disease-causing mutation and display normal karyotypes.
Publication
Journal: Frontiers in Neuroscience
January/28/2021
Abstract
Congenital central hypoventilation syndrome (CCHS) is a genetic disorder of neurodevelopment, with an autosomal dominant transmission, caused by heterozygous mutations in the PHOX2B gene. CCHS is a rare disorder characterized by hypoventilation due to the failure of autonomic control of breathing. Until now no curative treatment has been found. PHOX2B is a transcription factor that plays a crucial role in the development (and maintenance) of the autonomic nervous system, and in particular the neuronal structures involved in respiratory reflexes. The underlying pathogenetic mechanism is still unclear, although studies in vivo and in CCHS patients indicate that some neuronal structures may be damaged. Moreover, in vitro experimental data suggest that transcriptional dysregulation and protein misfolding may be key pathogenic mechanisms. This review summarizes latest researches that improved the comprehension of the molecular pathogenetic mechanisms responsible for CCHS and discusses the search for therapeutic intervention in light of the current knowledge about PHOX2B function.
Keywords: CCHS; PHOX2B; autonomic dysregulation; breathing disorder; congenital central hypoventilation syndrome; desogestrel; polyalanine expansions.
Publication
Journal: Indian Journal of Critical Care Medicine
January/8/2020
Abstract
Congenital central hypoventilation syndrome (CCHS) is characterized by shallow breathing during sleep due to negligible ventilatory sensitivity to hypercarbia and hypoxemia. It is diagnosed using a genetic test for PHOX2B mutation, which is not easily available. Neurally adjusted ventilatory assist (NAVA) is a spontaneous ventilatory mode that was designed basically for better adapting the ventilator to the patient by using electrical activity of diaphragm (EAdi) signals. We report a case of a 6-month-old infant who presented with recurrent apneas, where differential decrease in EAdi discharges during sleep using NAVA served as an early clue to the diagnosis of CCHS. Definitive diagnosis was later confirmed by genetic testing.

How to cite this article
Rauf A, Gupta D, Sachdev A, Gupta N, Gupta S, Kumar P, et al. Neurally Adjusted Ventilatory Assist: An Early Clue to Diagnosis of Congenital Central Hypoventilation Syndrome. IJCCM 2019;23(11):536-537.

Publication
Journal: BMC Pediatrics
July/14/2020
Abstract
Background: Congenital central hypoventilation syndrome (CCHS) is a rare disease characterized by sleep apnea. Anoxia often occurs soon after birth, and it is important to prevent anoxia-mediated central nervous system complications; however, data on the relationship between respiratory management and the prognosis for intellectual development of patients with CCHS is not well yet investigate.
Methods: We performed a retrospective chart review cohort study of patients with CCHS in Japan. We investigated the risk and prognostic factors for developmental outcomes and examined the disease in terms of its symptoms, diagnosis, complications, and treatment.
Results: Of the 123 patients with CCHS included in the survey, 88 patients were 6 years old and older. They were divided into two group based on their intelligence quotient. Those treated using positive-pressure ventilation via tracheostomy in the first three months of life had a better developmental prognosis than those managed via tracheostomy after three months of age and those treated by ventilation using mask (OR = 3.80; 95% CI: 1.00-14.37, OR = 4.65; 95% CI: 1.11-19.37). There was no significant difference in physical development (P = 0.64).
Conclusions: The best respiratory treatment for patients with CCHS is ventilation via tracheostomy, initiated ideally before the age of three months.
Keywords: Apnea; Bilevel continuous positive airway pressure; Infant; Intellectual development; PHOX2B; Tracheostomy.
Publication
Journal: Journal of Clinical Sleep Medicine
August/3/2020
Abstract
Study objectives: Congenital central hypoventilation syndrome (CCHS) is caused by the PHOX2B mutation and predominantly diagnosed during the neonatal period. Although late-onset (LO)-CCHS and paired-like homeobox 2B (PHOX2B) mutation carriers have been reported, the features of these disease states in adults remain uncertain. This study aimed to identify the characteristics of adult-onset CCHS and PHOX2B-mutation carriers in adult.
Methods: We mainly searched the PubMed/Medline and Cochrane Databases and classified our target patients into 2 groups: group A, symptomatically diagnosed with LO-CCHS in adulthood; group B, adult PHOX2B-mutation carriers. Then, clinical characteristics including the onset, treatment, long-term course, and pattern of the PHOX2B mutation in both groups were analyzed. Additionally, a new adult-case of LO-CCHS was added to the analysis.
Results: Group A was comprised of 12 patients. The onset triggers of illness included a history of respiratory compromise following general anesthesia and respiratory tract infections. All patients in Group A had 20/25 polyalanine repeat mutations (PARM) and required some chronic ventilatory support at least during sleep, including portable positive pressure ventilator via tracheostomy or non-invasive positive pressure ventilation (NPPV). In these patients with ventilatory support during sleep, sudden death or poor prognosis were not reported. Group B was comprised of 33 adults from 24 families with PHOX2B-mutations. Nine patients in Group B were confirmed with the diagnosis of CCHS. Although PARM 20/25 represented the most common gene mutation, diverse mutations, including mosaicism, were observed. Hypoventilation of several cases in group B were underdiagnosed by overnight polysomnography without monitoring for CO₂.
Conclusion: Alveolar hypoventilation with unknown origin can be caused by the PHOX2B mutation even in adult cases. Both the identification of the PHOX2B-mutation and the incorporation of capnography in polysomnography are important for adult cases with unexplained alveolar hypoventilation or asymptomatic mutation carriers.
Keywords: CCHS; PHOX2B; congenital central hypoventilation syndrome; late-onset CCHS; polysomnography; transcutaneous carbon dioxide monitoring.
Publication
Journal: Case reports in pediatrics
April/10/2020
Abstract
Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder of an autonomic nervous disorder that affects breathing. It is characterized by respiratory insufficiency secondary to insensitivity to hypoxemia and hypercarbia, particularly during sleep leading to persistent apnea. We report four individuals across two generations harboring heterozygous 25 polyalanine repeats mutations (PARMs) in PHOX2B with a varying degree of phenotypic clinical manifestations. Two family members who reported to be "asymptomatic" were subsequently diagnosed with CCHS, based on genetic testing, obtained because of their family history. Genetic studies in the family including a mother and three offsprings revealed in-frame five amino acid PARMs of PHOX2B consistent with CCHS in addition to full clinical assessment. All affected individuals had evidence of hypercapnia on blood gas analysis with PCO2 in the range of 32-70 (mean; 61). Nocturnal polysomnogram revealed evidence of hypoventilation in two individuals (1 offspring and mother) with the end-tidal CO2 median of 54. Magnetic resonance imaging of brain revealed no abnormalities in the brain stem. There was no evidence of cor pulmonale on echocardiograms in all individuals. Neuropsychological testing was conducted on all four patients; two patients (mother and 1 offspring) had normal results, while the other two offspring exhibited some impairments on neuropsychological testing. This case series emphasizes the importance of screening first-degree relatives of individuals with confirmed CCHS to minimize complications associated with long-term ventilatory impairment. It also suggests that some patients with CCHS should undergo neuropsychological evaluations to assess for cognitive weaknesses secondary to their CCHS.
Publication
Journal: Journal of Clinical Sleep Medicine
January/29/2020
Abstract
Diaphragm pacing (DP) by phrenic nerve stimulation is a modality of chronic ventilatory support in individuals with congenital central hypoventilation syndrome (CCHS). We report a 9-year-old girl with CCHS who uses DP without tracheostomy during sleep. Her parents report hypoxemia and hypercapnia related to positional changes of the body during sleep requiring frequent adjustment of pacer settings. Overnight polysomnography was performed to titrate DP settings that showed adequate gas exchange in the supine position, but intermittent hypoxemia and hypercapnia were noted in the left decubitus position without obstructive sleep apnea occurring. Subsequently, the DP amplitude settings were increased during polysomnography thereby identifying and treating positional hypoxemia and hypercapnia in various body positions. Our case emphasizes the importance of polysomnography in children with CCHS using DP to monitor for sleep disordered breathing and titration of DP settings to achieve optimal oxygenation and ventilation with different body positions during sleep.
Publication
Journal: Stem Cell Research
June/4/2021
Abstract
Congenital central hypoventilation syndrome (CCHS) is characterized by an alteration of the ventilatory response to hypercapnia and hypoxia, and is classically presented in neonates with abnormalities of the autonomic nervous system. Here, we generated human induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells (PBMCs) isolated from a male patient clinically diagnosed with CCHS. These iPSC lines carry a heterozygous RET mutation (c.2608-125C > T), express pluripotency markers, have the capacity to differentiate into the normal teratoma tissue, retain the RET mutation and display the normal karyotype, which will also provide a useful resource to study the pathogenesis of CCHS.
Publication
Journal: Pulmonology
August/26/2021
Abstract
Background: Annual in-hospital respiratory evaluations (AREs) during wakefulness and sleep are recommended to assess ventilatory requirements in patients with congenital central hypoventilation syndrome (CCHS) aged ≥2-3 years based on expert consensus. This study aimed to determine if AREs in patients with CCHS led to changes in ventilatory management. Methods: Retrospective review of patients with CCHS who underwent AREs with or without polysomnography between 2017 and 2019 was conducted. Clinical symptoms, results of AREs, and subsequent changes in ventilatory management were analyzed. Results: We identified 10 patients with CCHS aged 4-20 years. All patients required assisted ventilation (AV) only during sleep delivered by positive pressure ventilation via tracheostomy (n = 7) or diaphragm pacing (n = 3). In total, 7 (70%) patients had abnormal oxygenation and/or ventilation requiring changes in ventilator settings or duration of AV. Six patients required an increase in settings and/or duration of AV, and only 1 patient required a decrease in ventilator settings. Two patients had awake hypercapnia during a routine outpatient visit that improved following increase in ventilator settings and a period of continuous AV. One patient who was previously ventilator-dependent only during sleep was identified to require 16 h per day of AV. All patients (n = 3) who reported symptoms such as headache or oxygen desaturations during sleep required an increase in ventilator settings. Conclusion: We report a high prevalence of changes in AV management following an ARE. Our results demonstrate the importance of regular AREs in patients with CCHS to assess their ventilatory requirements and optimize AV.
Keywords: CCHS; congenital central hypoventilation syndrome; diaphragm pacing; polysomnogram; ventilator.
Publication
Journal: Journal of Clinical Sleep Medicine
September/23/2020
Abstract
Diaphragm pacing (DP), a modality of ventilatory support in children with congenital central hypoventilation syndrome (CCHS), generates respiration using the patient's own diaphragm as the respiratory pump. We report a 14-year-old boy with CCHS who uses DP with an uncapped tracheostomy during sleep. Polysomnography to titrate DP settings identified artifacts occurring in regular intervals coinciding with the onset of inspiration during all sleep stages in several channels including legs, snore, and electrocardiogram. Clinicians interpreting polysomnograms performed during DP should become familiar with the multichannel artifacts due to DP impulses. We also identified that our patient was hyperventilated on home DP settings that led to adjustment of DP settings during the polysomnogram to achieve optimal oxygenation and ventilation. Our case also highlights the utility of polysomnography to ensure optimal gas exchange during sleep in children with CCHS using DP.
Keywords: CCHS; artifact; congenital central hypoventilation syndrome; diaphragm pacing; polysomnogram.
Publication
Journal: Pediatr Investig
August/27/2020
Abstract
Introduction: Congenital central hypoventilation syndrome (CCHS) is a rare disorder characterized by alveolar hypoventilation and autonomic system dysregulation secondary to mutations of the PHOX2B gene. Treatment consists of assisted ventilation using positive-pressure ventilators via tracheostomy, bi-level positive airway pressure (BPAP) via a noninvasive interface, negative-pressure ventilators, or diaphragm pacing. The long-term use of BPAP in younger children at home has been less frequently reported.
Case presentation: We present a case of a 2-month-old infant with CCHS who was successfully managed by BPAP without the need for tracheostomy and followed up for 7 years.
Conclusion: CCHS is a rare disease that manifests as nocturnal desaturation and carbon dioxide retention in early life. Noninvasive ventilation can be successfully used in young infants via an appropriate mask.
Keywords: Congenital central hypoventilation syndrome; Noninvasive ventilation; PHOX2B gene.
Publication
Journal: Pediatrics International
June/23/2020
Abstract
Background: Definitive diagnosis of congenital central hypoventilation syndrome (CCHS) is made by genetic testing. However, there are only a few examinations that supports to perform genetic testing. Electrical activity of the diaphragm (Edi) is a myogenic potential of the diaphragm and it reflects central respiratory drive in the respiratory center. We evaluated the function of the respiratory center in CCHS by Edi monitoring.
Methods: Edi monitoring was performed in 6 CCHS cases without mechanical ventilation. The monitoring time was 30 consecutive minutes from wakefulness to sleep. The TcPCO2 or EtCO2 and SpO2 were recorded simultaneously.
Results: Edi peak during wakefulness was 14.0 (10.3-21.0) µV and Edi peak during sleep was 6.7 (3.8-8.0) µV. Edi peak during sleep was significantly lower from Edi peak during wakefulness, and patients represented hypoventilation. Although TcPCO2 or EtCO2 increased due to hypoventilation, an increase in Edi peak that reflects central respiratory drive was not observed. ΔEdi/ΔCO2 was -0.06μV/mmHg. Maximum EtCO2 or TcPco2 was 51mmHg, and the average SpO2 was 91.5% during monitoring.
Conclusions: We confirmed that Edi monitoring could evaluate the function of respiratory center and reproduce hypoventilation of CCHS. The present study suggested that Edi monitoring is a valuable examination for proceeding genetic testing and it may lead to an early diagnosis of CCHS.
Keywords: congenital central hypoventilation syndrome; diagnostic method; early diagnosis; electrical activity of diaphragm; respiratory center function.
Publication
Journal: International Journal of Pediatric Otorhinolaryngology
April/5/2020
Abstract
Transitioning children with Congenital Central Hypoventilation Syndrome (CCHS) from nocturnal invasive ventilation via tracheostomy to noninvasive positive pressure ventilation (NIPPV) is challenging due to the leak caused by the tracheocutaneous fistula (TCF), resulting in insufficient ventilation. Decannulation and primary closure of the TCF with immediate transition to nocturnal NIPPV was performed in two children with CCHS at a tertiary care children's hospital. Neither child developed significant adverse effects such as pneumomediastinum or pneumothorax. This technique is a novel approach that may improve decannulation outcomes and aid transition to NIPPV in this patient population.
Publication
Journal: Frontiers in Pediatrics
July/8/2020
Abstract
Central hypoventilation (CH) is a quite rare disorder caused by some congenital or acquired conditions. It is featured by increased arterial concentration of serum carbon dioxide related to an impairment of respiratory drive. Patients affected by CH need to be treated by mechanical ventilation in order to achieve appropriate ventilation and oxygenation both in sleep and wakefulness. In fact, in severe form of Congenital Central Hypoventilation Syndrome (CCHS) hypercarbia can be present even during the day. Positive pressure ventilation via tracheostomy is the first therapeutic option in this clinical condition, especially in congenital forms. Non-Invasive ventilation is a an option that must be reserved for more stable clinical situations and that requires careful monitoring over time.
Keywords: arterial concentration of serum carbon dioxide; central apnea; central hypoventilation; children; non-invasive ventilation.
Publication
Journal: Molecular genetics & genomic medicine
October/12/2020
Abstract
Background: Mutations in the PHOX2B gene cause congenital central hypoventilation syndrome (CCHS), a rare autonomic nervous system dysfunction disorder characterized by a decreased ventilatory response to hypercapnia. Affected subjects develop alveolar hypoventilation requiring ventilatory support particularly during the non-REM phase of sleep. In more severe cases, hypoventilation may extend into wakefulness. CCHS is associated with disorders characterized by the defective migration/differentiation of neural crest derivatives, including aganglionic megacolon or milder gastrointestinal phenotypes, such as constipation. Most cases of CCHS are de novo, caused by heterozygosity for polyalanine repeat expansion mutations (PARMs) in exon 3. About 10% of cases are due to heterozygous non-PARM missense, nonsense or frameshift mutations.
Methods: We describe a three-generation Maltese-Caucasian family with a variable respiratory/Hirschsprung phenotype, characterized by chronic constipation, three siblings with Hirschsprung disease necessitating surgery, chronic hypoxia, and alveolar hypoventilation requiring non-invasive ventilation.
Results: The sequencing of PHOX2B revealed a novel heterozygous c.241+2delT splice variant in exon 1 that segregates with the CCHS/Hirschsprung phenotype in the family. The mutation generates a non-functional splice site with a deleterious effect on protein structure and is pathogenic according to ACMG P VS1, PM2, and PP1 criteria.
Conclusion: This report is significant as no PHOX2B splice-site mutations have been reported. Additionally, it highlights the variability in clinical expression and disease severity of non-PARM mutations.
Publication
Journal: Sleep Medicine Clinics
November/1/2020
Abstract
The need for long-term noninvasive positive pressure ventilation (NiPPV) in children with chronic respiratory failure is rapidly growing. This article reviews pediatric-specific considerations of NiPPV therapy. Indications for NiPPV therapy can be categorized by the cause of the respiratory failure: (1) upper airway obstruction, (2) musculoskeletal and/or neuromuscular disease, (3) lower respiratory tract diseases, and (4) control of breathing abnormalities. The role of NiPPV therapy in select rare conditions (spinal muscular atrophy, congenital central hypoventilation syndrome, cerebral palsy, scoliosis, and Chiari malformations) is also reviewed.
Keywords: Cerebral palsy (CP); Chiari malformations; Chronic respiratory failure; Congenital central hypoventilation syndrome (CCHS); Noninvasive ventilation; Pediatrics; Scoliosis; Spinal muscular atrophy (SMA).
Publication
Journal: Acta Neurologica Belgica
April/26/2020
Abstract
Central hypoventilation in adult patients is a rare life-threatening condition characterised by the loss of automatic breathing, more pronounced during sleep. In most cases, it is secondary to a brainstem lesion or to a primary pulmonary, cardiac or neuromuscular disease. More rarely, it can be a manifestation of congenital central hypoventilation syndrome (CCHS). We here describe a 25-year-old woman with severe central hypoventilation triggered by analgesics. Genetic analysis confirmed the diagnosis of adult-onset CCHS caused by a heterozygous de novo poly-alanine repeat expansion of the PHOX2B gene. She was treated with nocturnal non-invasive ventilation. We reviewed the literature and found 21 genetically confirmed adult-onset CCHS cases. Because of the risk of deleterious respiratory complications, adult-onset CCHS is an important differential diagnosis in patients with central hypoventilation.
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